Journal
ATHEROSCLEROSIS
Volume 198, Issue 1, Pages 198-207Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2007.09.034
Keywords
ezetimibe; simvastatin; LDL receptor; HMG-CoA reductase; gene expression; PCSK9; NPC1L1
Funding
- Medical Research Council [MC_U120074271] Funding Source: researchfish
- MRC [MC_U120074271] Funding Source: UKRI
- Medical Research Council [MC_U120074271] Funding Source: Medline
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Objective: The combination of simvastatin, an HMG-CoA reductase inhibitor, and ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, decreases cholesterol synthesis and absorption and reduces circulating LDL-cholesterol concentrations. The molecular mechanisms underlying the pronounced lipid-lowering effects of this combination have not been fully elucidated in humans. Methods and results: One center, prospective, randomized, parallel three-group study in 72 healthy men (mean age 32 19 years, mean body mass index 25.7 +/- 3.2 kg/m(2)). Each group of twenty-four subjects received a 14-day treatment with either ezetimibe (10mg/day), simvastatin (40 mg/day) or their combination. Lipid levels, the ratio of non-cholesterol sterols to cholesterol concentrations (used as markers of cholesterol synthesis and absorption), cell surface LDL receptor (LDLR) protein as well as LDLR and HMG-CoA reductase gene expression in mononuclear blood cells were measured at baseline and at the end of the study. LDL-C decreased in all groups. Simvastatin decreased, ezetimibe increased and their combination had no effect on HMG-CoA reductase activity. Simvastatin and the combination of ezetimibe and simvastatin increased the HMG-CoA reductase and LDLR gene expression while ezetimibe had no effect. The cell surface LDLR protein expression remained unchanged in all groups. The combination of ezetimibe and simvastatin increased the expression of the serine protease proprotein convertase subtilisin/kexin 9 (PCSK9), an enzyme shown to down-regulate LDLR protein levels. Conclusions: The co-administration of ezetimibe and simvastatin abrogates the ezetin-tibe-induced increase in cholesterol synthesis and up-regulates the LDLR gene but not protein expression, an effect possibly mediated through a parallel upregulation of PCSK9 expression. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
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